1. Field of the Invention
Alcohol intoxication and dependence are serious health problems worldwide. Acute alcohol intoxication can seriously impair an individual's motor function, causing temporary incapacity which exposes the individual and others to potential accidents. Long term alcohol dependence can cause mental and physical disabilities which are detrimental to the individual and society. The problem is exacerbated by physical dependence on the alcohol which results in "alcohol withdrawal syndrome" as the individual ceases alcohol consumption. Alcohol withdrawal syndrome is characterized by tremors, weakness, sweating, hyperflexia, and, in the worst case, delirium tremens.
For these reasons, it would be highly desirable to provide methods to prevent both acute intoxication and long term alcohol dependence as well as for reversing established dependence. It would be particularly desirable if methods could be found which could facilitate withdrawal from long term alcohol dependence by reducing or eliminating the symptoms of alcohol withdrawal syndrome.
2. Description of the Background Art
Ethanol-induced changes in cAMP signal transduction appear to play a role in the acute and chronic effects of ethanol. See, for example, Nagy et al. (1988) Proc. Natl. Acad. Sci. USA 85:6973-6976; Gordon et al. (1986) Proc. Natl. Acad. Sci. USA 83:2105-2108; Valverius et al. (1987) Mol. Pharmac. 32:217-227; and Charness et al. (1988) Biochem. Biophys. Res. Comm. 155:138-143. Ethanol acutely increases receptor-stimulated cAMP levels in NG108-15 neuroblastoma.times.glioma hybrids (Gordon et al. (1986) supra.). In contrast, chronic exposure to ethanol causes a decrease in receptor-dependent cAMP levels (Gordon et al. (1986) supra. and Charness et al. (1988) supra.). This reduction appears to be significant in chronic alcoholism since cells from alcoholics exhibit decreases in both adenosine receptor-stimulated and PGE.sub.1 receptor-stimulated cAMP levels (Nagy et al. (1988) supra.; and Diamond et al. (1987) Proc. Natl. Acad. Sci USA 84:1413-1416.
Dar et al. have investigated the effects of certain adenosine antagonists (including caffeine, theophylline, and isobutylmethylxanthine on acute and chronic alcohol intoxication. Dar et al. (1985) Life Sciences 33:P1363-1374, set forth that theophylline ameliorated certain symptoms of intoxication while having no effect on others, depending on the time between theophylline administration and ethanol injection. Dipyridamole (which inhibits cellular adenosine uptake) was demonstrated to have a potentiating effect on certain symptoms of ethanol intoxication. Dar and Wooles (1986) Life Sciences 39:1429-1437, describe the effect of administration of caffeine, isobutylmethylxanthine, and theophylline over a 10-day period to mice. The intoxicating effect of ethanol was increased in mice fed isobutylmethylxanthine and caffeine, while theophylline appeared to have no effect. Dar et al. (1987) Psychopharmacology 91:1-4 demonstrates significant potentiation of ethanol-induced ataxia (loss of motor control) in mice pretreated with caffeine, theophylline, and isobutylmethylxanthine.